Fludarabine Based RIC for Bone Marrow Failure Syndromes

Patients 0-22 years with acquired aplastic anemia or a diagnosed inherited bone marrow failure syndrome, and a fully Human leukocyte antigen (HLA)-matched (10/10) related donor.

Inclusion Criteria:

Patient:

Ages 0-22 years at time of enrollment

Diseases:

Patients with severe or very severe acquired AA, defined by:

Bone marrow biopsy demonstrating cellularity of <25% (at least 2 weeks from last dose of G-CSF), in addition to 2 of the following: absolute neutrophil count (ANC) <500/µL, platelets < 20,000/µL and absolute reticulocytes <40,000/µL
Negative evaluation for inherited bone marrow failure conditions and negative evaluation for dysplasia or cytogenetic abnormalities associated with myelodysplastic syndromes
Patients with concurrent paroxysmal nocturnal hemoglobinuria (PNH) clones are eligible, as long as they meet criteria for severe or very severe aplastic anemia as defined above

Patients with clinically diagnosed and/or genetically proven iBMF syndromes, resulting in chronic red blood cell or platelet-transfusion dependence and/or an absolute neutrophil count <500/µL. These disorders include, but are not limited to:

Fanconi Anemia
Dyskeratosis Congenita
Severe Congenital Neutropenia
Diamond-Blackfan Anemia
Congenital Dyserythropoietic/Sideroblastic Anemias
Congenital Amegakaryocytic Thrombocytopenia
Shwachman-Diamond Syndrome
Lansky or Karnofsky performance >60
HLA matched related donor available.
No active untreated infection
Females of childbearing potential must have negative pregnancy test.

Organ Function:

Serum creatinine <1.5xupper limit of normal for age Hepatic: Transaminases <5x normal
Cardiac shortening fraction >27%
Bilirubin <2.5x normal (unless elevation due to Gilberts disease).

Donor Selection Criteria:

Donor selection will comply with U.S. Food and Drug Administration's Code of Federal Regulations
Fully HLA-matched related donor.
Donor must be at least 6 months of age
Donor suitable for bone marrow collection and meets eligibility for donation, including fulfilling infectious disease criteria as per SOP, including HIV, Hepatitis B, Hepatitis C Polymerase chain reaction (PCR) negative.
If subject has confirmed iBMF syndrome, donor must be evaluated for this disorder and testing must be negative
Children's Hospital of Philadelphia (CHOP) bone marrow transplant (BMT) procedures apply for determining donor eligibility, including donor screening and testing for relevant communicable disease agents and diseases.
Donor evaluation and collection procedure as per CHOP Standard Operating Procedures (SOP)

Exclusion Criteria:

Uncontrolled bacterial, viral or fungal infections
HLA matched related donor unable to donate bone marrow.
No eligible fully HLA-matched related donor
Pregnant females
Patients with a clinical diagnosis of Myelodysplastic syndrome (MDS) defined by combination of bone marrow dysplasia and classic cytogenetic lesion (Monosomy 7, Trisomy 8 eg.), with or without excess blasts.
Patients with PNH without underlying bone marrow aplasia